title: Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren's syndrome before disease onset.
abstract: To date, little is known about why exocrine glands are subject to immune cell infiltrations in Sjögren's syndrome (SjS). Studies with SjS-prone C57BL/6.NOD-Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks before disease onset and suggested the potential involvement of inflammatory caspases (caspase-11 and -1). To determine whether inflammatory caspases are critical for the increased epithelial cell death before SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent upregulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity and apoptotic epithelial cells in the SMX of C57BL/6.NOD-Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for interleukin (IL)-1beta and IL-18 secretion, resulted in an elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD-Aec1Aec2 were not colocalized with caspase-11, indicating that caspase-11 functions in a noncell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of lipopolysaccharide (LPS-) and interferon (IFN)-gamma-stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting a pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset.
authors.affiliation: Department of Oral and Maxillofacial Surgery and Diagnostic Sciences (OMSDS), University of Florida College of Dentistry (UFCD), Gainesville, FL , USA.
authors.forename: Marievic
authors.initials: M
authors.lastname: Bulosan
authors.forename: Kaleb M
authors.initials: KM
authors.lastname: Pauley
authors.forename: Kyumee
authors.initials: K
authors.lastname: Yo
authors.forename: Edward K L
authors.initials: EK
authors.lastname: Chan
authors.forename: Joseph
authors.initials: J
authors.lastname: Katz
authors.forename: Ammon B
authors.initials: AB
authors.lastname: Peck
authors.forename: Seunghee
authors.initials: S
authors.lastname: Cha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D012463:Saliva / Q000276:immunology / Q000378:metabolism; D012469:Salivary Glands / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1